HPV is a small, circular, and double-stranded DNA virus belonging to the Papillomaviridae family, having an icosahedral structure and no envelope. There are over 200 different virus types in this group. HPV types appear to be type-specific immunogens in that a neutralizing immunity to infection to one type of papillomavirus does not confer immunity against another type of HPV.
In humans, different HPV types cause distinct diseases. While most HPV infections are benign causing warts on areas of the body including the hands, feet and genitals. HPV has been indicated as the human biologic carcinogen at a higher risk of developing certain types of cancers, comprising penile, vaginal, vulva, anal, and oropharyngeal cancers.
HPV types 1, 2, 3, 4, 7, 10 and 26-29 cause benign warts in both normal and immunocompromised individuals. HPV types 5, 8, 9, 12, 14, 15, 17, 19-25, 36 and 46-50 cause flat lesions in immunocompromised individuals. HPV types 6, 11, 34, 39, 41-44 and 51-55 cause nonmalignant condylomata of the genital or respiratory mucosa. HPV types 6 and 11 are the causative agents for more than 90% of all condyloma (genital warts) and laryngeal papillomas. Other HPV types of particular interest with respect to cancer are types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68. HPV types 16 and 18 are those which have the highest association with cervical cancer. HPV types 31 and 45 are the types with the next highest association with a cancer risk. HPV types 16 and 18 cause epithelial dysplasia of the genital mucosa and are associated with the majority of in situ and invasive carcinomas of the cervix, vagina, vulva and anal canal.
HPV is perhaps best known for causing nearly 100% of cervical cancer cases, which remains the fourth most-deadly cancer in women worldwide. There are upwards of thirty subtypes of HPV and some of these subtypes have been associated with cervical cancer. Around 80% of cervical cancer cases are associated with HPV types 16 (˜60%) and 18 (˜20%).
The genome of HPV contains open reading frames (ORFs) called E1-E7 and L1 and L2: “E” means early, and “L” means late. L1 and L2 encode capsid proteins of HPV. The early (E) genes are associated with functions comprising virus replication and cell transformation.
The L1 protein is the major capsid protein having a molecular weight of from 55 to 60 kilo-Dalton (kDa) when measured by polyacrylamide gel electrophoresis. The L2 protein is the minor capsid protein which also has an estimated molecular weight of from 55 to 60 kDa and an apparent molecular weight of from 75 to 100 kDa. Most of the L2 protein is internal to the L1 protein. The L2 proteins are highly conserved among different papillomaviruses, especially the 10 basic amino acids at the C-terminus. The L1 ORF is highly conserved among different papillomaviruses.
HPV prophylactic vaccines have been developed and mainly used as a preventative measure against infectious diseases. Indeed, there have been several successes in the development of the prophylactic vaccines which have effectively prevented healthy, vaccinated patients by or associated with HPV infections, targeting the major capsid protein of the virus-like particles (VLPs). VLPs are morphologically similar to authentic virions and are capable of inducing high titres of neutralizing antibodies upon administration into animals or humans. Because VLPs do not contain the potentially oncogenic viral genome, they present a safe alternative to the use of live virus in HPV vaccine development. For this reason, the L1 and L2 genes have been identified as immunological targets for the development of prophylactic and therapeutic vaccines for HPV infections and associated diseases.
After HPV viral DNA is integrated in to the host's genome, the early genes (E1, E2, E4 and, E5) and the late genes (L1 and L2) can be deleted. The E2 gene is a negative regulator for HPV oncogenes E6 and E7; therefore, these oncogenes serve as a hallmark of HPV-associated diseases because they are often expressed at elevated levels in infected cells. The oncoproteins E6 and E7 are functionally required for the initiation and maintenance of the diseases and serve as non-self, foreign proteins. For these reasons, the oncoproteins E6 and E7 have received significant attention as ideal targets for HPV therapeutic vaccines.
VLP-based vaccines have proven to be effective at inducing immune responses in human patients vaccinated with bivalent HPV types 16 and 18 prophylactic vaccines, quadrivalent HPV types 6, 11, 16, and 18 VLP-based vaccines, and nine-valent HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 prophylactic vaccines. For example, CERVARIX, GARDASIL® and GARDASLL® 9 are available polyvalent vaccines marketed for prevention of HPV.
CERVARIX is a bivalent prophylactic vaccine indicated for the prevention of HPV (types 16 and 18). CERVARIX is approved for use in females 9 through 25 years of age for the prevention of cervical cancer, cervical intraepithelial neoplasia or worse and adenocarcinoma in situ caused by HPV types 16 and 18. However, CERVARIX has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a woman has previously been exposed through sexual activity.
GARDASIL® is a commercially available quadrivalent prophylactic vaccine having activity against HPV (types 6, 11, 16, and 18). GARDASIL® is indicated in girls and women 9 through 26 years of age for the prevention of cervical, vulvar, vaginal, and anal cancer caused by HPV types 16 and 18, genital warts caused by HPV types 6 and 11, and cervical intraepithelial neoplasia, cervical adenocarcinoma in situ, cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia, vaginal intraepithelial neoplasia, anal intraepithelial neoplasia caused by HPV types 6, 11, 16, and 18. GARDASIL® is also indicated in boys and men 9 through 26 years of age for the prevention of anal cancer caused by HPV types 16 and 18, genital warts caused by HPV types 6 and 11, and anal intraepithelial neoplasia caused by HPV types 6, 11, 16, and 18.
GARDASIL® 9 is another commercially available nine-valent vaccine marketed for prevention of HPV (types 6, 11, 16, 18, 31, 33, 45, 52, and 58). GARDASIL® 9 is indicated in girls and women 9 through 26 years of age for the prevention of cervical, vulvar, vaginal, and anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58, genital warts caused by HPV types 6 and 11, and cervical intraepithelial neoplasia, cervical adenocarcinoma in situ, cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia, vaginal intraepithelial neoplasia, anal intraepithelial neoplasia caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. GARDASIL® 9 is also indicated in boys and men 9 through 26 years of age for the prevention of anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58, genital warts caused by HPV types 6 and 11, and anal intraepithelial neoplasia caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.
These preventive vaccines are typically administered for systemic action, being injected into a patient subcutaneously or intramuscularly (e.g., deltoid), remote from any particular target, such as the cervix. Moreover, they are generally accepted to be effective prior to exposure to HPV and are not commonly known to be effective for treatment after exposure to, or infection with, HPV.
There are limited treatment options for patients with established HPV infections and associated diseases. In addition, the HPV infections remain extremely common globally, representing a significant health burden. Therefore, there is an urgent need to develop effective and innovative treatments to clear HPV infections and HPV-associated diseases.
HPV antigen-derived proteins are processed by dendritic cells (DCs) and presented by major histocompatibility complex (MHC) class I or class II molecules to initiate CD8+ or CD4+ T cell immune responses, respectively. Protein-based vaccines have been shown to be safe and easy to produce.
The present disclosure relates to a combination therapy comprising a therapeutic vaccine and a recombinant vaccinia virus for treating HPV-associated diseases. The present disclosure further relates to a method of administration of a combination therapy comprising a therapeutic vaccine and a recombinant vaccinia virus for treating HPV associated diseases.